Modular access to nimbolide could provide the opportunity to develop agents that target poly-ADP-ribose polymerase 1 (PARP1) for the treatment of BRCA-deficient cancers. Now, a convergent strategy is reported, in which late-stage coupling of a pharmacophore-containing building block and a diversifiable hydrazone unit enables the preparation of nimbolide and various analogues.
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References
Murai, J. et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72, 5588–5599 (2012). This paper reports that PARPis induce PARP trapping.
Li, P. et al. Nimbolide targets RNF114 to induce the trapping of PARP1 and poly-ADP-ribosylation-dependent DNA repair factors. Preprint at bioRxiv https://doi.org/10.1101/2022.10.04.510815. (2022). This preprint reports that by inhibiting RNF114, nimbolide causes PARP1 trapping and synthetic lethality in BRCA-deficient cancers.
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This is a summary of: Deng, H. et al. Synthesis of nimbolide and its analogues and their application as poly(ADP-ribose) polymerase-1 trapping inducers. Nat. Synth. https://doi.org/10.1038/s44160-023-00437-w (2023).
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Exploration of nimbolide and its analogues as PARP trappers enabled by chemical synthesis. Nat. Synth 3, 301–302 (2024). https://doi.org/10.1038/s44160-023-00438-9
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DOI: https://doi.org/10.1038/s44160-023-00438-9
